Investigating the role of cancer-cell intrinsic cGAS/STING pathway activation in immune evasion by Nf1 deficient ovarian tumors
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Date
Authors
Li, Deyang
Keyword
cGAS/STING pathway , Cancer immunology , High grade serous ovarian carcinoma , Tumor immune microenvironment , In-vivo models
Abstract
High-grade serous ovarian carcinoma (HGSC), the deadliest gynecological malignancy, exhibits universal mutations in TP53 (~96%) alongside frequent mutations in other DNA damage repair (DDR) genes like BRCA1/2 (~20%), PTEN (~6%), and NF1 (~20%). Among these, loss of NF1 (and PTEN) are associated with poor prognosis and acquired resistance to platinum-based chemotherapy. DDR deficiency is associated with distinct tumor immune microenvironment (TIME) states from non-infiltrated to infiltrated. While the TIME of BRCA1/2 and PTEN deficient tumors have been defined, immune profiles of NF1 deficient tumors have not been fully characterized. Establishing these links could help counter chemoresistance and inform optimal use of immunotherapies in HGSC.
NF1 loss activates rat sarcoma virus (Ras) and mitogen-activated protein kinase (MAPK) pathways, which can increase programmed death-ligand 1 (PD-L1) expression. Interestingly, the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is also linked to MAPK signaling and upregulation of PD-L1. We thus hypothesized that constitutive cancer-cell intrinsic STING pathway activation contributes to the poor prognosis of Nf1 deficient HGSC by driving PD-L1 mediated immune evasion. C57BL/6 mice were injected with ID8 Trp53-/-;Nf1-/- murine ovarian cancer cells to characterize the TIME. Nf1 deficient tumors exhibited high immune cell infiltration and increased expression of genes associated with STING pathway activation and immune checkpoints. To determine STING pathway’s role in the associated TIME states, ID8 Trp53-/-;Nf1-/-;Sting1-/- derivative cell lines were then generated using Clustered-Regularly-Interspaced-Short-Palindromic-Repeats (CRISPR) technology. The functional properties of resulting cell lines were characterized through a wound healing and cytokine secretion assay. Ascites from mice injected with ID8 Trp53-/-;Nf1-/-;Sting1-/- showed an increase in B cells, myeloid-derived-suppressor cells (MDSCs), and programmed cell death protein 1 (PD-1) positive T cells at early stages of disease progression. Sting1 loss in ID8 Trp53-/-;Nf1-/- cells increased secretion of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1), and C-X-C motif chemokine ligand 1 (CXCL1).
Taken together, cancer-cell intrinsic STING pathway activation may alter the associated TIME and contribute to the aggressiveness of Nf1 deficient tumors. Findings from this study provide novel information on the role of cancer cell intrinsic STING pathway in mediating an aggressive disease phenotype in HGSC.